The mechanisms of myocardial failure in the hereditary cardiomyopathy of the Syrian hamster are being explored in this cooperative collaborative effort. At the Albert Einstein College of Medicine (A. Bhan), alterations in myofibrillar proteins and proteases which specifically remove light chains from the myosin molecule are to be studied relative to demonstrated reductions in myosin ATPase activity. Contractile activity (J. Krueger, A.L. Sorenson, B.A. Wittenberg & E.H. Sonnenblick) will be studied in single cardiac cells and skinned fibers where complex geometry and tissue heterogeneity are removed. Activation, contraction and relaxation will be explored at the sarcomere level in single cells while calcium sensitivity will be assessed in myofibrillar preparations. The electrophysiology (R. Aronson) of this model is to be defined for the first time. The ultrastructural and cytological changes (S. Factor & R. Bhan) during phases of myolysis, healing, hypertrophy and ultimate dilatation will be defined with special attention to membranes. At Medical College of Virginia (W.Weglicki & D. Pang), defects in excitation-contraction coupling will be studied at various disease stages using highly purified membrane systems encompassing sarcolemma and sarcoplasmic reticulum. Sarcolemmal (Na-K ions) ATPase, adenyl cyclase, calcium binding and uptake will be studied in fragmented sarcoplasmic reticulum. Electron spin resonance spectroscopy will be used to follow changes in membrane structure, using lipid-directed spin labels. At the University of Toronto School of Medicine (M. Sole & C.C. Liew). nuclear histones will be studied as a factor in altered synthetic processes. The myopathic hamsters which are bred with careful quality control and provided to participating investigators form a common experimental substrate for all these studies. Informational interchange and review of scientific progress is attested to by 6 years of productive collaborative and cooperative work. This proposal is the sole support for the maintenance of this unique cardiomyopathic model which has provided a highly useful predictable study model of myopathic heart failure.